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Nucleotide excision repair polymorphisms and survival outcome for patients with metastatic breast cancer

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Abstract

Purpose

Inter-individual variations in treatment efficacy may be influenced by polymorphisms in DNA repair genes. We investigated the association of 3 functional polymorphisms in the nucleotide excision repair (NER) pathway with survival outcome of 95 patients with metastatic breast cancer (MBC) treated with DNA-damaging chemotherapy.

Methods

ERCC1 8092 C/A, ERCC2 Asp312Asn and ERCC2 Lys751Gln were determined using Taqman-based genotyping assays. Genotype associations with breast cancer-specific survival (BCSS) and progression-free survival (PFS) were evaluated using Kaplan–Meier estimates and hazard ratios calculated using Cox regression analysis. Tests for trend were conducted by calculating P-values for the HR coefficient in proportional hazards regression models.

Results

ERCC2 Lys751Gln was significantly associated with BCSS (median: 24.8 months for AA/AC combined and 14.2 months for CC, HR: 1.9 (95% CI 1.06–3.26)). Median BCSS decreased with increasing number of designated adverse genotypes for the 3 polymorphisms (Ptrend = 0.003). Risk estimates for PFS were nonsignificantly elevated and were significantly elevated for BCSS for patients with 2 (HR = 2.21, 95% CI: 1.04–4.72) or 3 (HR = 6.67, 95% CI: 2.19–20.29) adverse genotypes. In treatment subgroup analysis, risk estimates for BCSS were significantly elevated for patients with 3 adverse genotypes treated with cyclophosphamide, mitoxantrone and vinblastine (HR: 11.9, 95% CI 1.77–79.51) and Ptrend = 0.02 for increasing number of adverse genotypes. Risk of progression was significantly increased for patients with 1 adverse genotype treated with cyclophosphamide, mitoxantrone and carboplatin (HR: 3.5, 95% CI 1.19–10.6) and Ptrend = 0.02 for increasing number of adverse genotypes.

Conclusion

Polymorphisms in NER pathway may impact survival outcome for patients with MBC following treatment with DNA-damaging chemotherapy. These results provide support for a polygenic pathway approach for assessing the prognostic and predictive potential of polymorphisms in treatment outcome.

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Acknowledgments

We thank the Northern Cancer Research Foundation for their support of this research.

Conflict of interest statement

We declare that we have no conflict of interest in relation to this work.

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Authors and Affiliations

  1. Sudbury Regional Hospital, Regional Cancer Program, 41 Ramsey Lake Rd, Sudbury, ON, P3E 5J1, Canada

    Mary A. Bewick, Robert M. Lafrenie & Michael S. C. Conlon

  2. Northern Ontario School of Medicine, Sudbury, ON, Canada

    Robert M. Lafrenie

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  1. Mary A. Bewick
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  2. Robert M. Lafrenie
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Correspondence to Mary A. Bewick.

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Bewick, M.A., Lafrenie, R.M. & Conlon, M.S.C. Nucleotide excision repair polymorphisms and survival outcome for patients with metastatic breast cancer. J Cancer Res Clin Oncol 137, 543–550 (2011). https://doi.org/10.1007/s00432-010-0915-7

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  • DOI: https://doi.org/10.1007/s00432-010-0915-7

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